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Impaired T‐cell development in the absence of Vav1 and Itk
Author(s) -
Raberger Julia,
Boucheron Nicole,
Sakaguchi Shinya,
Penninger Josef M.,
Ellmeier Wilfried
Publication year - 2008
Publication title -
european journal of immunology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.272
H-Index - 201
eISSN - 1521-4141
pISSN - 0014-2980
DOI - 10.1002/eji.200838388
Subject(s) - cd8 , thymocyte , t cell , biology , microbiology and biotechnology , cancer research , immunology , immune system
Abstract Vav1 and the Tec family kinase Itk act in similar T‐cell activation pathways. Both molecules interact with members of the Cbl family of E3 ubiquitin ligases, and signaling defects in Vav1 −/− T cells are rescued upon deletion of Cbl‐b. In this study we investigate the relation between Itk and Cbl‐b or Vav1 by generating Itk/Cbl‐b and Itk/Vav1 double‐deficient mice. Deletion of Cbl‐b in Itk −/− CD4 + T cells restored proliferation and partially IL‐2 production, and also led to a variable rescue of IL‐4 production. Thus, Itk and Vav1 act mechanistically similarly in peripheral T cells, since the defects in Itk −/− T cells, as in Vav1 −/− T cells, are rescued if cells are released from the negative regulation mediated by Cbl‐b. In addition, only few peripheral CD4 + and CD8 + T cells were present in Vav1 −/− Itk −/− mice due to severely impaired thymocyte differentiation. Vav1 −/− Itk −/− thymocyte numbers were strongly reduced compared with WT, Itk −/− or Vav1 −/− mice, and double‐positive thymocytes displayed increased cell death and impaired positive selection. Therefore, our data also reveal that the combined activity of Vav1 and Itk is required for proper T‐cell development and the generation of the peripheral T‐cell pool.